1. Polmonite comunitaria grave: etiologia e trattamento Marco Falcone Marco Falcone Dipartimento Sanità Pubblica e Malattie Infettive Scuola Superiore di Studi Avanzati “Sapienza” Università di Roma

2. What is severe pneumonia? Rello J, Crit Care 2008, 12(Suppl 6):S2 Requiring ICU admission

3. Criteria for severe CAP Major criteria Minor criteriaOther factors to consider Invasive mechanical ventilation Respiratory rate ≥ 30 breaths/min Hypoglycemia (in nondiabetic patients) Septic shock with the need of vasopressor PaO 2 / FiO 2 ≤250 Acute alcoholism/alcoholic withdrawal, Multilobar infiltrates Hyponatremia Confusion/disorientation Unexplained metabolic acidosis or elevated lactate level Uremia (BUN level ≥20 mg/dl)Cirrhosis Leukopenia (WBC count < 4000 cells/mm 3 ) Asplenia Thrombocytopenia (platelet count <100000 cells/mm 3 ) Hypotermia (core temperature <36°) Hypotension requiring aggressive fluid resuscitation Clin Infect Dis 2007; 44 Suppl 2:S27-72.

4. Interaction bacteria-host VIRULENCE Attachment (pili, adhesin, biofilm) Invasiveness (hyaluronidase, coagulase, etc) Esotoxins Inhibition to phagocytosis MICROBIAL LOAD MECHANICAL BARRIERS INNATE/ADAPTIVE IMMUNITY

5. Clinical case 1 65-year- old German woman who arrived in Rome from Frankfurt Transfer from the airport to the hospital for sudden-onset hemoptysis, dyspnea, which had rapidly worsened over 2–3 The patient developed acute respiratory failure requiring ventilator support; hyponatremia; increased levels of serum creatinine, lactate dehydrogenase, lactic acid; leukopenia (1800 cells/mm3); and increased levels of C-reactive protein (>400 mg/mL) and d-dimer (>2,000 μg/mL). Computed tomography of the chest showed patchy opacification throughout the lungs and multifocal confluent parenchymal opacities. Legionella urinary antigen negative, start piperacillin-tazobactam 4.5 g i.v. every 6 hours plus azytromycin 500 mg i.v. q24 Progressive deterioration of gas exchange, septic shock, death after 6 hours from the arrival to the hospital

6. Emerg Infect Dis 2014; 20: 98-101

7. Clinical case 2 20 years old woman affected by adult Still disease was admitted in our hospital for fever (38°C) from 3-4 days, cough, skin rash and general malaise. She was on therapy with Anakinra, an interleukin-1 (IL-1) receptor antagonist plus corticosteroids Rx at admission: limited area of consolidation in the right lobe. pO2 64 mmHg. Start ceftriaxone plus clarithromycin and transfer in reumathology medical ward. After few hours from hospital admission rapid worsening of clinical condition, fever >40°C, hypotension, sudden cardiac arrest requiring transfer to an intensive care unit WBC >51.000 cells/mm3, PaO2/FiO2 < 150, lactate 10, Hypotension resistant inotropic drugs - septic shock

8. Mechanical ventilation, inotropic drugs. Gram stain from blood cultures gram positive lancet-shaped cocci Growth of Streptococcus pneumoniae Clinical course

9. Mice treated intraperitoneally with anakinra (IL- 1R−/−) died within 7 days postinfection while all wild-type mice survived J Infect Dis 2013; 207: 50-60. Interleukin-1 promotes coagulation, which is necessary for protective immunity in the lung against Streptococcus pneumoniae infection

10. J Clin Immunol. 2014 Apr;34(3):267-71. J Infect Dis 2012; 205:1849–57.

11. Principles for management of pneumonia: point of view of the Infectious Diseases specialist Cover most frequent pathogens Measure the risk for MDR Reduce cardiovascular complications Reduce the systemic inflammatory response to infection (SIRS to septic shock & MOF) Provide for the shortest time to clinical stability Early switch to oral therapy Decide the optimal duration of antibiotic therapy

12. N Engl J Med 2015; 373: 415-27

13. Epidemiological classification of pneumonia Possible infecting pathogens: Pseudomonas aeruginosa MRSA Acinetobacter spp Enterobacteriaceae (ESBL+) Legionella pneumophila Start empirical treatment - Third or fourth generation cephalosporin (ceftazidime or cefepime) or Carbapenem (imipenem, meropenem) or Piperacillin/tazobactam plus - Quinolone (levofloxacin or ciprofloxacin) or Aminoglycoside plus - Linezolid or vancomycin OR ceftobiprole Potential treatment regimen - Respiratory fluoroquinolone or - beta-lactam + macrolide Hospital-acquired pneumonia Community- acquired pneumonia Common infecting pathohens - Streptococcus pneumoniae - Mycoplasma pneumoniae - Chlamydia pneumoniae - Haemophilus influenzae - Legionella species - Respiratory viruses - Antibiotic-susceptible Enterobacteriaceae

14. 17.8% p = 0.02 p > 0.05 CAP HCAP HAP 18.4% 6.7% Ann Intern Med 2009; 150: 19-26.

15. Who are the patients at risk for MDR pathogens while living in the community? HCAP or CAP?

16. PLoS One 2015;10:e0119528.

18. Distributions of MDR bacteria

19. PLoS One 2015;10:e0119528. Factors associated with isolation of MDR bacteria

20. PLoS One 2015;10:e0119528.

22. AUC 0.76

23. BMC Infect Dis 2013;13: 94.

24. Pneumonia: only an infectious syndrome?

25. Clinical case 3 65-year- old man, diabetic, previous myocardial infarction treated with percutaneous angioplasty Admission for fever, dyspnea, purulent sputum, chest pain. Acute respiratory failure requiring non-invasive ventilation, increased levels of serum creatinine (2.1), lactic acid, leukocytosis (18000 cells/mm3), and increased levels of C-reactive protein (245 mg/mL). Chest radiograph: bilateral pneumonia. Legionella urinary antigen positive, levofloxacin 750 mg i.v. + plus azytromycin 500 mg i.v. q24 At day 3 improvement of gas exchange, but comparison of ventricular tachycardia, ST-tract elevation, troponin 1.12 (n.v. < 0.05), diagnosis of acute myocardial infarction.

26. J Am Coll Cardiol. 2014; 64:1917–25.

28. Platelet Activation Is Associated With Myocardial Infarction in Patients With Pneumonia J Am Coll Cardiol. 2014; 64:1917–25.

30. Estimated survival during hospitalization using Kaplan- Meier survival analysis. J Am Heart Assoc 2015;4:e001595

31. Thorax 2015; 70:961-6

34. Variables Survived n=108 (%) Non-survived n=80 (%) p Age, median76.878.20.086 HCAP41 (37.9)49 (61.2)<0.001 ≥ 2 comorbidities71 (65.7)55 (68.5)0.07 Charlson Comorbidity Index, median3.63.90.46 Delirium24 (22.2)55 (68.5)<0.001 Cardiovascular events during hospitalization12 (11.1)37 (46.2)<0.001 PaO2/FiO2 ratio <30025 (23.2)61 (76.2)<0.001 Platelets < 150.000 mm310 (9.2)12 (15)0.03 CRRT20 (18.5)19 (23.7)0.03 ARDS29 (26.8)35 (43.7)0.001 Bacteremia29 (26.8)33 (41.2)0.001 NIV use32 (29.6)36 (45)<0.001 Mechanical ventilation45 (41.6)44 (55)<0.001 SOFA score, median3.24.7<0.001 Use of inotropic agents108 (100%)80 (100%)1.0 Median length of hospitalization (days)19.822.30.07 Median length of therapy (days)14.116.40.001 Aspirin therapy55 (50.9)20 (25)<0.001 Steroid therapy66 (61.1)49 (61.2)0.91 Use of a macrolide57 (52.8)15 (18.7)<0.001 Aspirin plus macrolides therapy36 (33.3)10 (12.5)<0.001 Admission to ICU50 (46.3)45 (56.3)0.02 Septic shock from community-onset pneumonia: is there a role for aspirin + macrolides combination? Falcone M et al Intensive Care Medicine 2015 (in press)

35. Septic shock from community-onset pneumonia: is there a role for aspirin + macrolides combination? Falcone M et al Intensive Care Medicine 2015 (in press) Effect of aspirin and macrolide therapy alone and in combination after adjustment by propensity score

36. Septic shock from community-onset pneumonia: is there a role for aspirin + macrolides combination? Falcone M et al Intensive Care Medicine 2015 (in press)

37. Pneumonia: challenges for the future Falcone M et al (personal view)

38. Siemieniuk et al Ann Intern Med 2015; 163:519-528